Copper(II) and zinc(II) complexes with clinically used antifungal drug fluconazole (fcz), {[CuCl₂(fcz)₂]^.5H₂O}_n, 1, and {[ZnCl₂(fcz)₂]·2C₂H₅OH}_n, 2, were prepared and characterized by spectroscopic and crystallographic methods. The polymeric structure of the complexes comprises four fluconazole molecules monodentately coordinated via the triazole nitrogen and two chlorido ligands. With respect to fluconazole, complex 2 showed significantly higher antifungal activity against Candida krusei and Candida parapsilosis. All tested compounds reduced the total amount of ergosterol at subinhibitory concentrations, indicating that the mode of activity of fluconazole was retained within the complexes, which was corroborated via molecular docking with cytochrome P450 sterol 14α-demethylase (CYP51) as a target. Electrostatic, steric and internal energy interactions between the complexes and enzyme showed that 2 has higher binding potency to this target. Both complexes showed strong inhibition of C. albicans filamentation and biofilm formation at subinhibitory concentrations, with 2 being able to reduce the adherence of C. albicans to A549 cells in vitro. Complex 2 was able to reduce pyocyanin production in Pseudomonas aeruginosa between 10% and 25% and to inhibit its biofilm formation by 20% in comparison to the untreated control. These results suggest that complex 2 may be further examined in the mixed Candida-P. aeruginosa infections.

Drug resistance to existing anticancer agents is a growing clinical concern, with many first line treatments showing poor efficacy in treatment plans of some cancers. Resistance to platinum agents, such as cisplatin, is particularly prevalent in the treatment of ovarian cancer, one of the most common cancers amongst women in the developing world. Therefore, there is an urgent need to develop next generation of anticancer agents which can overcome resistance to existing therapies. We report a new series of organoruthenium(II) complexes bearing structurally modified pyrithione ligands with extended aromatic scaffold, which overcome platinum and adriamycin resistance in human ovarian cancer cells. The mechanism of action of such complexes appears to be unique from that of cisplatin, involving G₁ cell cycle arrest without generation of cellular ROS, as is typically associated with similar ruthenium complexes. The complexes inhibit the enzyme thioredoxin reductase (TrxR) in a model system and reduce cell motility towards wound healing. Importantly, this work highlights further development in our understanding of the multi-targeting mechanism of action exhibited by transition metal complexes.

In a search for novel antimicrobial metal-based therapeutic agents, mononuclear gold(III) complexes 1–7 of the general formula [AuCl₃(azole)], where azole stands for imidazole (im, 1), 1-isopropylimidazole (ipim, 2), 1-phenylimidazole (phim, 3), clotrimazole (ctz, 4), econazole (ecz, 5), tioconazole (tcz, 6) and voriconazole (vcz, 7) were synthesized, characterized and biologically evaluated. In all complexes, the corresponding azole ligand is monodentately coordinated to the Au(III) via the imidazole or triazole nitrogen atom, while the remaining coordination sites are occupied by chloride anions leading to the square-planar arrangement. In vitro antimicrobial assays showed that the complexation of inactive azoles, imidazole, 1-isopropylimidazole and 1-phenylimidazole, to the Au(III) ion led to complexes 1–3, respectively, with moderate activity against the investigated strains and low cytotoxicity on the human normal lung fibroblast cell line (MRC-5). Moreover, gold(III) complexes 4–7 with clinically used antifungal agents clotrimazole, econazole, tioconazole and voriconazole, respectively, have, in most cases, enhanced antimicrobial effectiveness relative to the corresponding azoles, with the best improvement achieved after complexation of tioconazole (6) and voriconazole (7). The complexes 4–7 and the corresponding antifungal azoles inhibited the growth of dermatophyte Microsporum canis at 50 and 25 μg mL⁻¹. Gold(III) complexes 1–3 significantly reduced the amount of ergosterol in the cell membrane of Candida albicans at the subinhibitory concentration of 0.5 × MIC (minimal inhibitory concentration), while the corresponding imidazole ligands did not significantly affect the ergosterol content, indicating that the mechanism of action of the gold(III)–azole complexes is associated with inhibition of ergosterol biosynthesis. Finally, complexes 5 and 6 significantly reduced the production of pyocyanin, a virulence factor in Pseudomonas aeruginosa controlled by quorum sensing, and increased cell survival after exposure to this bacterium. These findings could be of importance for the development of novel gold(III)-based antivirulence therapeutic agents that attenuate virulence without pronounced effect on the growth of the pathogens, offering a lower risk for resistance development.

Dimethyl 6-(pyrazine-2-yl)pyridine-3,4-dicarboxylate (py-2pz) was used as a ligand for the synthesis of new copper(II) and silver(I) complexes, [CuCl₂(py-2pz)]₂ (1), [Cu(CF₃SO₃)(H₂O)(py-2pz)₂]CF₃SO₃·2H₂O (2), [Ag(py-2pz)₂]PF₆ (3) and {[Ag(NO₃)(py-2pz)]·0.5H₂O}_n (4). The complexes were characterized by spectroscopic and electrochemical methods, while their structures were determined by single crystal X-ray diffraction analysis. The X-ray analysis revealed the bidentate coordination mode of py-2pz to the corresponding metal ion via its pyridine and pyrazine nitrogen atoms in all complexes, while in polynuclear complex 4, the heterocyclic pyrazine ring of one py-2pz additionally behaves as a bridging ligand between two Ag(I) ions. DFT calculations were performed to elucidate the structures of the investigated complexes in solution. The antimicrobial potential of the complexes 1–4 was evaluated against two bacterial (Pseudomonas aeruginosa and Staphylococcus aureus) and two Candida (C. albicans and C. parapsilosis) species. Silver(I) complexes 3 and 4 have shown good antibacterial and antifungal properties with minimal inhibitory concentration (MIC) values ranging from 4.9 to 39.0 μM (3.9–31.2 μg mL⁻¹). All complexes inhibited the filamentation of C. albicans and hyphae formation, while silver(I) complexes 3 and 4 had also the ability to inhibit the biofilm formation process of this fungus. The binding affinity of the complexes 1–4 with calf thymus DNA (ct-DNA) and bovine serum albumin (BSA) was studied by fluorescence emission spectroscopy to clarify the mode of their antimicrobial activity. Catechol oxidase biomimetic catalytic activity of copper(II) complexes 1 and 2 was additionally investigated by using 3,5-di-tert-butylcatechol (3,5-DTBC) and o-aminophenol (OAP) as substrates.

The clinically used antifungal agents, econazole, voriconazole and clotrimazole, were successfully applied in the synthesis of novel silver(i)-azole complexes with significantly improved anti-Candida activity in respect to the parent organic drugs.

Thymoquinone (TQ), a natural compound with antimicrobial and antitumor activity, was used as the starting molecule for the preparation of 3-aminothymoquinone (ATQ) from which ten novel benzoxazole derivatives were prepared and characterized by elemental analysis, IR spectroscopy, mass spectrometry and NMR (¹H, ¹³C) spectroscopy in solution. The crystal structure of 4-methyl-2-phenyl-7-isopropyl-1,3-benzoxazole-5-ol (1a) has been determined by X-ray diffraction. All compounds were tested for their antibacterial, antifungal and antitumor activities. TQ and ATQ showed better antibacterial activity against tested Gram-positive and Gram-negative bacterial strains than benzoxazoles. ATQ had the most potent antifungal effect against Candida albicans, Saccharomyces cerevisiae and Aspergillus brasiliensis. Three benzoxazole derivatives and ATQ showed the highest antitumor activities. The most potent was 2-(4-fluorophenyl)-4-methyl-7-isopropyl-1,3-benzoxazole-5-ol (1f). Western blot analyses have shown that this compound inhibited phosphorylation of protein kinase B (Akt) and Insulin-like Growth Factor-1 Receptor (IGF1R β) in HeLa and HepG2 cells. The least toxic compound against normal fibroblast cells, which maintains similar antitumor activities as TQ, was 2-(4-chlorophenyl)-4-methyl-7-isopropyl-1,3-benzoxazole-5-ol (1e). Docking studies indicated that 1e and 1f have significant effects against selected receptors playing important roles in tumour survival.